Department of Chemistry, National Tsing-Hua University, Hsinchu 30013, Taiwan.
Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan.
ACS Appl Bio Mater. 2021 Mar 15;4(3):2475-2489. doi: 10.1021/acsabm.0c01438. Epub 2021 Feb 9.
-Hydroxy--(4-arylbutanamido)benzamides (HABAB) belong to one class of histone deacetylase inhibitors (HDACi), which regulate deacetylation of lysine residue's amino group in histone, which results in chromatin constriction. In addition, transcriptional knockdown of the genetic loci possessing the suppressor genes of tumor occurs. A tripodal, HABAB-capped gallamide dendron possessing thiol anchoring unit was prepared by the click method. The resultant hydrophilic dendritic unit was easily attached on the outer layer of CdSe/ZnS (i.e., core/shell type) quantum dots by thiolate-Zn interaction, as supported via H NMR spectroscopic analysis of the conjugate with its original property of fluorescence. The resulting, water-miscible nanohybrid (nano-HTPB) which bore trivalent, peripheral HABABs as the HDACi was efficiently taken up by cells of lung cancer and transported into the nuclei of cells in 3 h, as confirmed by confocal microscopy analysis. The concentration levels of 50% inhibition (IC) after 48 h incubation of the nano-HTPB for A549 and H1299 lung cancer cell lines were 14 and 18 nM, respectively, which were about 150-fold lower than those of the parent HTPB analogues. Nano-HTPB at 20 nM induced the knockdown of cell cycle at second growth/mitosis (i.e., G2/M) transition, which eventually led to apoptosis of lung cancer cells, demonstrating that the nano-HTPB was much more potent in inhibiting lung cancer cell growth in a synergistic manner than the parent HTPB analogues. In addition, the dendritic HABAB-capped nanohybrid, nano-HTPB, is more effective than the parent HTPB analogues both in vitro and in vivo. Furthermore, the nano-HTPB is more effective than the parent HTPB to increase the acetylation level of proteins related to histone and nonhistone like p53 and tubulin. Our results confirmed that covalent encapsulation of quantum dots with peripheral, triantennary HDACis represented a feasible strategy for synergistic drug delivery with enhanced biological effects.
羟-(4-芳基丁酰胺基)苯甲酰胺（HABAB）属于组蛋白去乙酰化酶抑制剂（HDACi）的一类，可调节组蛋白赖氨酸残基氨基的去乙酰化，导致染色质紧缩。此外，还会发生携带肿瘤抑制基因的遗传基因座的转录敲低。通过点击法制备了具有巯基锚固单元的三足状、HABAB 封端的三苯胺半乳糖酰胺树枝状大分子。所得的亲水性树枝状单元通过硫醇-Zn 相互作用很容易附着在 CdSe/ZnS（即核/壳型）量子点的外层，通过与原始荧光性质的共轭物的 1H NMR 光谱分析得到证实。所得的水溶性纳米杂化物（nano-HTPB）具有作为 HDACi 的三价外围 HABAB，可有效地被肺癌细胞摄取，并在 3 小时内被运入细胞的核内，通过共聚焦显微镜分析得到证实。对于 A549 和 H1299 肺癌细胞系，在 48 小时孵育后 nano-HTPB 的 50%抑制浓度（IC）分别为 14 和 18 nM，分别比母体 HTPB 类似物低约 150 倍。浓度为 20 nM 的 nano-HTPB 诱导细胞周期在第二次生长/有丝分裂（即 G2/M）转换时出现阻滞，最终导致肺癌细胞凋亡，表明 nano-HTPB 比母体 HTPB 类似物更有效地协同抑制肺癌细胞生长。此外，树枝状 HABAB 封端的纳米杂化物 nano-HTPB 无论是在体外还是在体内，都比母体 HTPB 类似物更有效。此外，nano-HTPB 比母体 HTPB 更有效地增加与组蛋白和非组蛋白样 p53 和微管蛋白相关的蛋白质的乙酰化水平。我们的研究结果证实，用外围三价 HDACi 共价包封量子点代表了一种可行的策略，可用于协同药物输送，并增强生物学效应。
